Para-aminophenol type nonnarcotic analgesics/antipyretics have been known for over a century. They act to decrease fever by an effect on the hypothalamus leading to sweating and vasodilation and inhibit the effect of pyrogens on the hypothalamic heat-regulating centers. The mechanism of the analgesic action of these agents is not fully understood. Although this analgesic action was initially thought to be peripherally mediated, current evidence supports a central mode of action (Acetaminophen-induced hypothermia in mice: evidence for a central action of the parent compound. Massey, Thomas E.; Walker, Robin M.; McElligott, Timothy F.; Racz, William J. Dep. Pharmacol. Toxicol., Queen's Univ., Kingston, ON, Can. Toxicology (1982), 25(2-3), 187-200; Central analgesic effect of acetaminophen but not of aspirin. Piletta, Pierre; Porchet, Herve C.; Dayer, Pierre. Dep. Med., Univ. Hosp., Geneva, Switz. Clin. Pharmacol. Ther. (St. Louis) (1991), 49(4), 350-4.; Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Bjoerkman, R.; Hallman, K. M.; Hedner, J.; Hedner, T.; Henning, M. Pain (1994), 57(3), 259-64.). Suggested biochemistries for this central mode of action include interaction with the L-arginine-NO pathway (Piletta, ibid), modulation of brain serotonin receptor level (Acetaminophen-induced antinociception via central 5-HT2A receptors. Srikiatkhachorn, Anan; Tarasub, Naovarut; Govitrapong, Piyarat. Neurochem. Int. (1999), 34(6), 491-498.) or inhibition of COX-3 enzyme activity (N. V. Chandrasekharan, Hu Dai, K. Lamar Turepu Roos, Nathan K. Evanson, Joshua Tomsik, Terry S. Elton, and Daniel L. Simmons (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc. Natl. Acad. Sci. USA, 99:13926-13931, 2002). Inhibition of the COX-3 enzyme, recently cloned from brain, points to the possible inhibition by these agents of CNS prostaglandin synthesis. The antipyretic and analgesic effects of these compounds are comparable to those of aspirin.
Para-aminophenol type nonnarcotic analgesics have been used to control pain due to headache, earache, dysmenorrhea, arthralgia, myalgia, musculoskeletal pain, arthritis, immunizations, teething, tonsillectomy. They are also used to reduce fever in bacterial or viral infections and as a substitute for aspirin in upper GI disease, aspirin allergy, bleeding disorders, clients on anticoagulant therapy, and gouty arthritis.
Unexamined Japanese patent application 57007431 (Jan. 14, 1982) discloses various analgesic phenols. This application, however, does not disclose or suggest the compounds of the present invention.
U.S. Pat. No. 4,532,249 discloses derivatives of para-acylaminophenol having analgesic activity. This patent, however, does not disclose or suggest the compounds of the present invention.
U.S. Pat. No. 3,689,555 discloses norbornyl aminoacetanilides for uses in analgesics. This patent, however, does not disclose or suggest the compounds of the present invention.
International Patent Applications WO 96/32100 and WO 97/33860 disclose aminoalkyl-acetamides as analgesic agents. These applications, however, do not disclose or suggest the compounds of the present invention.
U.S. Pat. No. 5,554,636 discloses cyclicsulfonamidylalkylacetamides as analgesic agents. This patent, however, does not disclose or suggest the compounds of the present invention.
In view of their lack of ulcerative and anticoagulation effects, paraaminophenol type nonnarcotic analgesics fill a need in analgesic and antipyretic therapies in patients with problems related to GI and cardiovascular disorders, and there is thus a continuing need for new pharmaceutical compounds of this class.